Stabilized medicinal substances, a process for the preparation thereof, and stable medicinal formulations

ABSTRACT

Stabilized compounds of the formula I ##STR1## in which R, R 1 , R 2 , R 3 , R 4  and R 5  have the stated meanings, and a process for the preparation thereof, are described. The stabilized compounds are suitable for the manufacture of medicinal formulations.

Compounds of the formula I ##STR2## in which R is hydrogen, C₁ -C₄ -alkyl or phenyl,

R¹ represents C₁ -C₄ -alkyl or ##STR3## in which m is 1, 2, 3 or 4, and A and B are identical or different and denote hydrogen or C₁ -C₄ -alkyl,

R² is hydrogen, C₁ -C₄ -alkyl or benzyl,

R³ is hydrogen or C₁ -C₄ -alkyl, and

R⁴ and R⁵ denote, together with the atoms carrying them, a heterocyclic, mono-, bi- or tricyclic hydrogenated or partially hydrogenated ring system which has one nitrogen atom and 4 to 15 ring carbon atoms and which is optionally mono- or disubstituted by C₁ -C₄ -alkoxy,

represent valuable pharmaceuticals. They are, for example, inhibitors of angiotensin converting enzyme (ACE) and can be used to control high blood pressure of various etiologies. A nootropic action of these compounds has also been described (cf. German Offenlegungsschrift 3,610,391, corresponding to EP-A 0,243,645 and U.S. patent application Ser. No. 29,905). The compounds of the formula I are disclosed in, for example, EP-A 79,022 and EP-A 50,800; in addition, reference may also be made to the citations quoted in German Offenlegungsschrift 3,610,391.

The active substances of the formula I are preferably administered orally, and solid administration forms such as, for example, tablets, coated tablets or capsules are particularly suitable.

It has been found that active substances of the formula I, such as, for example, 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (ramipril), show a tendency to be unstable in pharmaceutical formulations, depending on the auxiliaries used, the manufacturing process and the storage.

The main product of decomposition which has been detected in pharmaceutical formulations is the diketopiperazine compound produced by condensation and having the following structure II ##STR4##

Accordingly, the main product of decomposition of ramipril is the diketopiperazine derivative of the formula IIa ##STR5##

It has been found that the stability can be influenced by the choice of suitable auxiliaries, and that a significant cause of decomposition is the mechanical stress associated with the manufacturing process, especially when the active substance, for example ramipril, is present in a mixture with auxiliaries.

The investigation which is summarized in the table below illustrates the decomposition-inducing effect of the mechanical stress, taking ramipril as example.

2.5 mg ramipril tablets/effect of mechanical stress on stability.

    ______________________________________                                         Diketopiperazine derivative of ramipril (%)                                    Duration and                                                                              2.5 mg    2.5 mg     2.5 mg                                         nature of stress                                                                          tablets   tablets    capsules                                       ______________________________________                                         3 mon. + 40° C.                                                                    13.6       7.6       4.0                                            6 mon. + 40° C.                                                                    22.8      12.0       6.4                                            manufacturing                                                                             dry       direct     filling with the                               process    granulation                                                                              compression                                                                               powdered mixture                               mechanical stress                                                                         high      moderate   low                                            ______________________________________                                    

The three formulations compared have the same composition and contain the following auxiliaries: mannitol, microcrystalline cellulose, and sodium stearylfumarate. The only difference is in the power of compression (mechan. stress) involved in the process.

The results clearly show that the mechanical stress is a significant decomposition-inducing factor.

It has also been found that the storage conditions influence the stability of the active substances of the formula I.

Decomposition is favored by increasing temperature and moisture and by the two effects of storage acting together.

The tendency of, for example, ramipril to decompose in formulations in which all the said influencing factors act together is revealed in the following comparative test:

Determinations were carried out of the contents of active substance after stress for

a) the active substance itself; uncompressed

b) ramipril tablets which contained several auxiliaries and had been exposed to mechanical stress (compression):

    ______________________________________                                                      Content relative to initial value                                 Duration and nature                                                                           Ramipril    Ramipril                                            of stress      active substance                                                                           tablets                                             ______________________________________                                         6 months + 40° C.                                                                      99%         56%                                                 6 months + 40° C.                                                                      96%         <20%                                                80% rel. hum.                                                                  ______________________________________                                    

Tablets and auxiliaries used

Lactose monohydrate, corn starch, microcrystalline cellulose, sodium starch glycolate, highly disperse silica, talc and magnesium stearate.

The results clearly show that, under the chosen test conditions, the stability of the uncompressed active substance is good. Only on compression (mechan. stress) with generally used tabletting auxiliaries and after exposure to heat and, especially, moisture is there a large decrease in the content of active substance.

The preferred presentation for the active substances of the formula I is the tablet, because of the possibility of individual adjustment of the dose and better patient compliance. The presentations are, as shown by the above results, extremely unstable, especially when

1. mechanical stress (power of compression)

2. tabletting auxiliaries

3. temperature

4. moisture

act together.

Whereas mechanical stresses are unavoidable in the manufacture of formulations in compressed form, attempts have been made to obtain stable formulations by changing the auxiliaries. Taking ramipril as example, it has been made possible to optimize the formula by choosing auxiliaries specifically for their compatibility with ramipril. This is illustrated by the following comparison after exposure to stress.

    ______________________________________                                                   1 mg ramipril tablets                                                          Content relative to initial value                                    Duration and nature        Formula 2                                           of stress   Formula 1      (optimized formula)                                 ______________________________________                                         6 months 40° C.                                                                     56%            88.5%                                               Auxiliaries Lactose monohydrate,                                                                          mannitol, micro-                                                maize starch, micro-                                                                          crystalline                                                     crystalline cellulose,                                                                        cellulose, Na                                                   Na starch glycolate,                                                                          stearylfumarate                                                 highly disperse silica,                                                        talc,                                                                          magnesium stearate                                                 ______________________________________                                    

However, this measure is not by itself sufficient to stabilize the tablet formulation. It has now been found, surprisingly, that a protective coating of the pure ramipril, which is prone to decompose, with polymeric film-formers counteracts the mechanical inactivation. These findings were surprising because even small amounts of coating sufficed to shield the active substance from mechanical stress.

It has additionally been found that stable tablets suitable for oral administration are obtained when the active substance of the formula I is mixed with a buffer which ensures that the pH which is set up in the formulation under the action of atmospheric humidity is in the weakly acid to weakly alkaline range (5.5 to 8.0).

Hence the invention relates to a method for the stabilization of active substances of the formula I, which comprises coating the active substance, or a mixture containing the active substance, with a polymeric protective film, or comprises mixing the active substance of the formula I with a physiologically tolerated buffer which ensures that a pH in the weakly acid to weakly alkaline range is set up in a formulation in the presence of moisture, and active substances of the formula I which have been stabilized by a polymeric protective film or by mixture with a buffer. The active substances of the formula I can be present as such or as physiologically tolerated salts.

The centers of chirality at the carbon atoms in formula I marked with an asterisk (*) preferably have the S configuration.

Active substances of the formula I in which R, R¹, R² and R³ have the following meanings:

R: methyl or phenyl,

R¹ : methyl or (CH₂)₄ --NH₂,

R² : hydrogen or ethyl,

R³ : hydrogen, and in which

R⁴ and R⁵ form, with the atoms carrying them, preferably the following ring systems ##STR6## where R³ is preferably hydrogen, are preferred.

Particularly suitable active substances are: ##STR7##

Protective coatings in concentrations of as little as 3 to 25%, preferably 5 to 15% (percent by weight relative to the active substance which is to be coated), are effective. It was not to be expected that even thin film coatings are able to shield the contents from the high mechanical stresses customary in the tabletting process (5 KN to 30 KN).

It was additionally surprising that the polymers provided for the protective coating can be used as aqueous solutions without having an adverse effect on the stability.

Examples of polymers suitable for the protective coating

Cellulose derivatives such as, for example, hydroxyproplycellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxyethylcellulose, ethylcellulose, cellulose acetate phthalate, cellulose acetate, polyvinyl acetate phthalate, polyvinylpyrrolidone, cationic and anionic polymers, copolymer with neutral character based on poly(meth)acrylic esters (Eudragit® E, Eudragit® E 30 D), anionic polymer of methacrylic acid and methyl methacrylate (Eudragit® L or S, Eudragit® L 30 D) and gelatin. In principle, all physiologically tolerated polymers are suitable.

The protective coating can be carried out by dispersing the active substance with the solution or dispersion of the film-former in a suitable kneader, mixer or mixer-granulator. The uniformly wetted composition is then forced through a screen and dried. The dried granules are once more passed through a screen and then used to manufacture capsules or tablets. A particularly uniform coating is obtained in a fluidized bed. The particles of active substance are sprayed in the stream of air with a solution or dispersion of the polymer and are dried. The coated granules of active substance can be used immediately after the drying process for filling capsules or for manufacturing tablets.

However, it is also possible to combine the two processes together by initially wetting the active substance with the solution or dispersion of the polymer in a kneader, mixer or mixer-granulator, and subsequently processing it by granulation to give homogeneous agglomerates which are then finally coated with the solution or dispersion of the polymer in a fluidized bed.

The active substances stabilized with a protective film by the method according to the invention can be processed to give capsules or compressed administration forms. Such products are stable by comparison with products which are manufactured with untreated active substance. This is revealed best by the example of tablets in which the diminution in stability by the mechanical stress during manufacture becomes evident after subsequent exposure to heat.

A stability comparison with a standard formula without protective coating is shown in the table which follows.

                  TABLE 1                                                          ______________________________________                                         2.5 mg ramipril tablets                                                        Stability comparison/stabilizing effect of a protective coating                Nature of stress: 6 months + 40° C.                                     Packaging: Glass tubes with tight screw closure                                                        Tablets manufactured                                                  Standard according to the                                       Composition in mg                                                                             formula  invention as in Example 5                              ______________________________________                                         uncoated pure ramipril                                                                        2.50     --                                                     87%* pure ramipril                                                                            --        2.87                                                   *contains 13% HPMC as film coating                                       

    microcrystalline                                                                              47.00    47.00                                                  cellulose                                                                      free-flowing mannitol                                                                         49.50    49.13                                                  Na stearylfumarate                                                                             1.00     1.00                                                  tablet weight  100.00   100.00                                                 compressive force                                                                             10,000 N 10,000 N                                               decomposition to the                                                                          12.72     1.87                                                  diketopiperazine                                                               breakdown product in %                                                         ______________________________________                                    

Table 2 which follows demonstrates that a relatively thin coating of ramipril is still effective even after lengthy stress.

                  TABLE 2                                                          ______________________________________                                         2.5 mg ramipril tablets                                                        Stability comparison                                                           Nature of stress: 12 months + 40° C.                                    Packaging: Glass tubes with tight screw closure                                                        Tablets manufactured                                                  Standard according to the                                       Composition in mg                                                                             formula  invention as in Example 6                              ______________________________________                                         uncoated pure ramipril                                                                         2.50    --                                                     94%* pure ramipril                                                                            --        2.66                                                   *contains 6% HPMC as film coating                                        

    microcrystalline                                                                              25.00    25.00                                                  cellulose                                                                      free-flowing mannitol                                                                         71.50    71.34                                                  Na stearylfumarate                                                                             1.00     1.00                                                  tablet weight  100.00   100.00                                                 compressive force                                                                             10,000 N 10,000 N                                               during tabletting                                                              decomposition to the                                                                          25.34     5.97                                                  diketopiperazine                                                               breakdown product in %                                                         ______________________________________                                    

On stabilization by admixture of a buffer, the latter is mixed either with the active substance or with the coated active substance, during which the active substance or the coated active substance is being granulated with a buffer solution or is present in the dispersion or solution of the polymeric substance when both types of stabilization are used simultaneously.

The pH set up in the formulation, such as, for example, a tablet, in the presence of moisture, such as, for example, atmospheric humidity or water, is between 5.5 and 8.0.

Examples of suitable buffer substances are: sodium dihydrogen phosphate dihydrate, trisodium citrate dihydrate, sodium carbonate, sodium hydrogen carbonate and tris-(hydroxymethyl)aminomethane.

It is advantageous if the buffer substance is used as an aqueous solution, by the active substance being either moistened uniformly in a suitable mixer, kneader or mixer-granulator and then granulated and dried, or sprayed in a fluidized bed and spray-granulated in this way. However, it is also possible to granulate a mixture of active substance and buffer substance with water in the manner described.

It has proved particularly advantageous if the stabilizing effect produced by mixture with buffer is combined with a protective coating of the particles of active substance by polymeric film-formers.

This is carried out most advantageously in such a way that the buffer substance is already dissolved in the medium intended for coating the particles and is applied together with the polymeric film-former to the surface of the active substance. The coating techniques described for coating the particles are used for this.

The stabilizing effect of buffer substances is illustrated by the comparison in the following table (Table 3).

                  TABLE 3                                                          ______________________________________                                         2.5 mg ramipril tablets                                                        Stability comparison/stabilizing effect on buffer substances                   Nature of stress: 3 months + 40° C.                                     Packaging: Glass tubes with tight screw closure                                                        Tablets manufactured                                                  Standard according to the                                       Composition in mg                                                                             formula  invention as in Example 7                              ______________________________________                                         pure ramipril   2.5      2.5                                                   tris(hydroxymethyl)-                                                                          --        2.5                                                   aminomethane                                                                   pregelatinized starch                                                                         51.5     49.0                                                   microcrystalline                                                                              45.0     45.0                                                   cellulose                                                                      Na stearylfumarate                                                                             1.0      1.0                                                   tablet weight  100.0    100.0                                                  compressive force                                                                             10,000 N 10,000 N                                               during tabletting                                                              pH after suspending                                                                            5.4      6.9                                                   in water                                                                       decomposition to                                                                               7.1      0.6                                                   diketopiperazine                                                               breakdown product in %                                                         ______________________________________                                    

USE EXAMPLES Example 1 Preparation of stabilized pure ramipril

87 parts by weight of pure ramipril are granulated in a fluidized bed apparatus with 13 parts by weight of hydroxypropylmethylcellulose, called HPMC hereinafter, as a 5% strength aqueous solution. Examples of suitable types are Pharmacoat® 606 or Methoce® E5 Premium. The process takes place in two sections, in which the pure ramipril is first granulated with one half of the HPMC solution and then coated with the second half of the 5% strength aqueous HPMC solution.

The drying temperature is about 50° C. The coated pure ramipril can be mixed with auxiliaries and used to fill capsules or compressed directly, without other granulation steps, to tablets.

Example 2 Preparation of stabilized pure ramipril

94 parts by weight of pure ramipril are dispersed in a suitable kneader, mixer or mixer-granulator with 6 parts by weight of HPMC as a 10% strength aqueous solution until a uniformly moistened composition results. The moist composition is passed through a screen with a mesh size of 1.2 mm and is then dried at about 40° C. The dried agglomerates are once more passed through a screen with a mesh size of 0.5 to 1 mm. The finished ramipril granules can be used to manufacture capsules or tablets.

Example 3 Preparation of stabilized pure ramipril

1 part by weight of pure ramipril and 1 part by weight of tris(hydroxymethyl)aminomethane buffer substance are mixed in a suitable mixer or mixer-granulator and then moistened with sufficient purified water to produce a uniformly wetted composition.

The moist composition is granulated in the manner described in Example 2.

Example 4 Preparation of stabilized pure ramipril

4 parts by weight of pure ramipril, 6 parts by weight of polyvinylpyrrolidone (for example Kollidon® K25) and 18.8 parts by weight of sodium carbonate are mixed in a suitable mixer or mixer-granulator and then moistened with sufficient purified water to produce a uniformly wetted composition. The moist composition is granulated in the manner described in Example 2.

Example 5 Manufacture of 10,000 2.5 mg ramipril tablets

28.7 g of 87% pure ramipril (contains 13% HPMC as film coating as in Example 1), 470 g of microcrystalline cellulose and 491.3 g of free-flowing mannitol are mixed. In a second step, 10 g of sodium stearylfumarate are mixed into this mixture. 1-kg of the mixture prepared in this way is compressed directly, without other granulation steps, to tablets having a final weight of 100 mg.

Example 6 Manufacture of 10,000 2.5 mg ramipril tablets

26.6 g of 94% pure ramipril (contains 6% HPMC as film coating as in Example 2), 250 g of microcrystalline cellulose and 713.4 g of free-flowing mannitol are mixed. In a second step, 10 g of sodium stearylfumarate are mixed into this mixture. 1 kg of the mixture prepared in this way is compressed directly, without other granulation steps, to tablets having a final weight of 100 mg.

Example 7 Manufacture of 10,000 2.5 mg ramipril tablets

50 g of 50% pure ramipril, prepared as in Example 3, 450 g of microcrystalline cellulose and 490 g of pregelatinized starch are mixed. In a second step, 10 g of sodium stearylfumarate are mixed into this mixture.

1 kg of the mixture prepared in this way is compressed directly, without other granulation steps, to tablets having a final weight of 100 mg.

Example 8 Manufacture of 10,000 5 mg ramipril tablets

63 g of ramipril stabilized as in Example 4, 250 g of microcrystalline cellulose and 667 g of free-flowing mannitol are mixed. In a second step, 20 g of sodium stearylfumarate are mixed into this mixture.

1 kg of this mixture are compressed directly, without other granulation steps, to tablets having a final weight of 100 mg.

Example 9 Preparation of stabilized pure enalapril

85 parts by weight of enalapril hydrogen maleate are granulated in a fluidized bed apparatus with 15 parts by weight of hydroxypropylmethylcellulose (HPMC) as a 5% strength aqueous solution in the manner indicated in Example 1. The coated pure enalapril can be mixed with auxiliaries and used to fill capsules or compressed directly, without other granulation steps, to tablets.

Example 10 Preparation of stabilized pure enalapril

90 parts by weight of enalapril hydrogen maleate are dispersed in a suitable kneader, mixer or mixer-granulator with 10 parts by weight of HPMC as an aqueous solution until a uniformly moistened composition is produced. The moist enalapril composition is granulated in the manner described in Example 2. The finished enalapril granules with a protective coating can be used to manufacture capsules or tablets.

Example 11 Manufacture of 10,000 2.5 mg enalapril tablets

29.4 g of 85% pure enalapril hydrogen maleate (contains 15% HPMC as film coating as in Example 9), 480 g of microcrystalline cellulose and 480.6 g of modified free-flowing starch are mixed. In a second step, 10 g of sodium stearylfumarate are mixed into this mixture. 1 kg of this mixture is compressed directly, without other granulation steps, to tablets having a final weight of 100 mg.

Example 12 Manufacture of 10,000 10 mg enalapril tablets

111.1 g of 90% pure enalapril hydrogen maleate (contains 10% HPMC as film coating as in Example 10), 480 g of microcrystalline cellulose and 398.9 g of modified free-flowing starch are mixed. In a second step, 10 g of sodium stearylfumarate are mixed into this mixture. 1 kg of this mixture is compressed directly, without other granulation steps, to tablets having a final weight of 100 mg. 

We claim:
 1. A stable pharmaceutical composition is compressed form containing a compound of the formula I ##STR8## in which R is hydrogen, C₁ -C₄ -alkyl or phenyl,R¹ represents C₁ -C₄ -alkyl or ##STR9## in which m is 1, 2, 3 or 4, and A and B are identical or different and denote hydrogen or C₁ -C₄ -alkyl, R² is hydrogen, C₁ -C₄ -alkyl or benzyl, R³ is hydrogen or C₁ -C₄ -alkyl, and R⁴ and R⁵ denote, together with the atoms carrying them, a heterocyclic, mono-, bi- or tricyclic hydrogenated or partially hydrogenated ring system which has one nitrogen atom and 4 to 15 ring carbon atoms and which is optionally mono- or disubstituted by C₁ -C₄ -alkoxy, or the physiologically tolerated salts thereof, which compound is in the form of an agglomerate and is stabilized with a polymeric protective coating, wherein the proportion by weight of the polymeric protective coating is 3 to 25% relative to said compound.
 2. Ramipril in the form of an agglomerate stabilized with a polymeric protective coating, wherein the proportion by weight of the polymeric protective coating is 3 to 25% relative to said ramipril.
 3. A process for the preparation of the composition of claim 1, which comprises coating said compound with an amount of a polymeric protective film sufficient so that the proportion by weight of the polymeric protective coating is 3 to 25% relative to said compound, and compressing said coated compound.
 4. The composition of claim 1, further containing a buffer.
 5. A process for the manufacture of the composition of claim 1, which comprises coating said compound or a mixture containing said compound with a polymeric protective film, wherein the proportion by weight of the polymeric protective coating is 3 to 25% relative to said compound, and compressing said coated compound or mixture.
 6. The process of claim 3, comprising the additional step of adjusting with a buffer the environment of the compound of formula I to a pH range from 5.5 to
 8. 7. The process of claim 5, wherein the compound of formula I is ramipril and wherein the proportion by weight of the protective coating is 5 to 15% relative to said compound.
 8. A method for the manufacture of a stable pharmaceutical formulation in compressed form, comprising incorporating the coated compound of claim 1 in said pharmaceutical formulation.
 9. The composition of claim 1, wherein the proportion by weight of the polymeric protective coating is 5 to 15% relative to said compound of formula I.
 10. The composition of claim 1, wherein the proportion by weight of the polymeric protective coating is 15% relative to said compound of formula I.
 11. The process of claim 3, further comprising mixing said compound with a physiologically tolerated buffer.
 12. The process of claim 6, wherein said pH range is from 6.5 to
 7. 13. The process of claim 5, wherein said compound is mixed with a suitable auxiliary.
 14. The process of claim 6, wherein the compound of formula I is ramipril.
 15. The process of claim 6, wherein said pH is adjusted by incorporating said buffer into said polymeric protective coating.
 16. The process of claim 7, wherein the proportion by weight of the protective coating is 15% relative to said compound.
 17. The composition of claim 9, wherein said compound of formula I is ramipril.
 18. The composition of claim 10, wherein said compound of formula I is ramipril.
 19. Ramipril of claim 2, wherein the proportion by weight of the polymeric protective coating is 5 to 15% relative to said ramipril.
 20. Ramipril of claim 19, wherein the proportion by weight of the polymeric protective coating is 15% relative to said ramipril. 